Naglazyme (recombinant human arysulfatase B, rhASB) is used in the treatment of MPS VI; it hydrolyzes the 6-sulfate residue from N-acetylgalactosamine-6-sulfate (GalNac6S) moieties found on the non-reducing ends of glycosaminoglycans, thus alleviating a degradation blockade found in Maroteaux-Lamy syndrome. Subsequent to commercialization of Naglazyme, several changes to the manufacturing process have been implemented to improve process performance. The requirements for demonstrating comparability differed depending on the type of changes that were implemented. This presentation will illustrate the additional characterization methods (physicochemical and biological) used at BioMarin to demonstrate the comparability of rhASB produced by the optimized manufacturing processes. Data presented will include primary sequence and carbohydrate structural determinations, but will focus primarily on successive modifications made to an activity assay through use of increasingly biomimetic substrates.

9:35 Incorporation of Non-Clinical Components into a Comparability Program

Non-clinical studies can be a key component of the comparability process in establishing that manufacturing process changes have not impacted either the safety or the efficacy of the impacted biotherapeutic product. The focus of this presentation will be on identifying the criteria for conducting a non-clinical study, study design considerations based on development stage-gates, selection of the appropriate species, establishing bioanalytical assay cross-validation, utilization of non-clinical data to project human comparability, key factors for consideration of conduct of human studies, and non-clinical studies in the comparability lifecycle planning. These aspects will be discussed in the context of a case study.

10:05 Comparability of Biopharmaceutical Glycosylation from Different Cell Expression Systems

Daryl Fernandes, Ph.D., Chief Executive Officer, Ludger Ltd.

In this short seminar we will address comparability issues relevant to companies that (a) are developing new versions of glycoprotein therapeutics and (b) want to explore alternative cell expression systems. The seminar follows from previous talks at this CHI meeting on determination of glycosylation critical quality attributes and comparability of glycosylation during product scale up. This will be an interactive session with time allowed for discussions. The focus will be on the commercial and regulatory issues faced by those companies brave enough to consider improving their drugs by switching to new production systems.

Continual improvement is an essential hallmark of process development. Such improvements often result in process changes that require demonstration of comparability between the drug substance/product pre- and post-change. Based on the stage of the drug development program and the type of change being introduced, the requirements for demonstration of comparability can be significantly different. In this talk, a case study will be presented where, in addition to analytical and pre-clinical testing, a clinical pharmacokinetic and pharmacodynamic comparability study was incorporated into the comparability protocol.

Keynote

11:40 Comparability Assessments During Clinical Development and Post-Approval

Process changes during clinical development are assessed using quantitative and qualitative methods, asking “what changes are observed, and what are the perceived impacts of those changes on safety or efficacy?” For commercial product quantitative assays, material from the new process or facility is assessed using ranges derived by statistical analysis of commercial lots. Profile comparisons and accelerated degradation studies also have pre-defined acceptance criteria. An escalation path is followed if the physico-chemical methods identify changes to certain characteristics. Some modifications to our current strategy are envisioned for products with a licensed Design Space.

CimziaTM is a recombinant, humanized, antibody Fab’ fragment with specificity for human TNF that has been approved in the US for therapeutic treatment of Rheumatoid Arthritis and Crohns Disease, and in the EU for Rheumatoid Arthritis. The CimziaTM Fab’ fragment is produced in Escherichia coli, chromatographically purified and then conjugated to polyethylene glycol (PEG). CMC development has encompassed various site, scale and manufacturing process changes, including changes to the primary recovery and downstream processing and formulation. A total of nine Drug Substance manufacturing processes demonstrated comparability with regard to consistency of manufacture and resulting quality and stability attributes. This presentation will describe the development and regulatory challenges in demonstrating analytical comparability of CimziaTM.

Expanded Comparability Protocols (eCP) offer an alternative regulatory approach to traditional post-approval change submissions. eCPs can be used to prospectively define change requirements for several products, facilities, and changes in a single post-approval submission. The eCP must first consider the scope and define appropriate limitations based upon the breadth of changes intended for the eCP. Process and product knowledge, Quality by Design (QbD) concepts, and Quality Risk Management (QRM) principles can then be leveraged to define appropriate comparability requirements. A case study describing the technical and regulatory considerations for the transfer of products between sites will be presented.

The goal of a comparability exercise is to ensure the quality, safety and efficacy of a drug after changes in the manufacturing process. Available guidance specific for biotechnology products delineates principles to consider when establishing comparability. During early phases of clinical development, comparability testing is generally not as extensive as for a product in pivotal clinical trial or for an approved product. However, some early phase changes can pose difficult challenges. Expectations regarding comparability exercises during the product lifecycle will be presented.